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Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum.

ABSTRACT: BACKGROUND:Hypnotics and general anaesthetics impair memory by altering hippocampal synaptic plasticity. We recently reported on a neurosteroid analogue with potent hypnotic activity [(3?,5?,17?)-3-hydroxyandrostane-17-carbonitrile; 3?-OH], which does not cause developmental neurotoxicity in rat pups. Here, we investigated the effects of 3?-OH on neuronal excitability in the subiculum, the major output structure of the hippocampal formation, and synaptic plasticity at two key hippocampal synapses in juvenile rats. METHODS:Biophysical properties of isolated T-type calcium currents (T-currents) in the rat subiculum were investigated using acute slice preparations. Subicular T-type calcium channel (T-channel) subtype mRNA expression was compared using qRT-PCR. Using electrophysiological recordings, we examined the effects of 3?-OH and an endogenous neuroactive steroid, allopregnanolone (Allo), on T-currents and burst firing properties of subicular neurones, and on the long-term potentiation (LTP) in CA3-CA1 and CA1-subiculum pathways. RESULTS:Biophysical and molecular studies confirmed that CaV3.1 channels represent the dominant T-channel isoform in the subiculum of juvenile rats. 3?-OH and Allo inhibited rebound burst firing by decreasing the amplitude of T-currents in a voltage-dependent manner with similar potency, with 30-80% inhibition. Both neurosteroids suppressed LTP at the CA1-subiculum, but not at the CA3-CA1 Schaffer collateral synapse. CONCLUSIONS:Neurosteroid effects on T-channels modulate hippocampal output and provide possible molecular mechanisms for the amnestic action of the novel hypnotic 3?-OH. Effects on T-channels in the subiculum provide a novel target for amnestic effects of hypnotics.

SUBMITTER: Joksimovic SM

PROVIDER: S-EPMC6549045 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum.

Joksimovic Srdjan M SM Izumi Yukitoshi Y Joksimovic Sonja Lj SL Tesic Vesna V Krishnan Kathiresan K Asnake Betelehem B Jevtovic-Todorovic Vesna V Covey Douglas F DF Zorumski Charles F CF Todorovic Slobodan M SM

British journal of anaesthesia 20190228 5

<h4>Background</h4>Hypnotics and general anaesthetics impair memory by altering hippocampal synaptic plasticity. We recently reported on a neurosteroid analogue with potent hypnotic activity [(3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile; 3β-OH], which does not cause developmental neurotoxicity in rat pups. Here, we investigated the effects of 3β-OH on neuronal excitability in the subiculum, the major output structure of the hippocampal formation, and synaptic plasticity at two key hippocampal ...[more]

PMID: 30916017

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Project description:Angelman syndrome (AS) is a debilitating neurogenetic disorder characterized by severe developmental delay, speech impairment, gait ataxia, sleep disturbances, epilepsy, and a unique behavioral phenotype. AS is caused by a microdeletion or mutation in the maternal 15q11-q13 chromosome region containing UBE3A gene. The hippocampus is one of the important brain regions affected in AS mice leading to substantial hippocampal-dependent cognitive and behavioral deficits. Recent studies have suggested an abnormal increase in the α1-Na/K-ATPase (α1-NaKA) in AS mice as the precipitating factor leading to the hippocampal deficits. A subsequent study showed that the hippocampal-dependent behavioral deficits occur as a result of altered calcium (Ca+2) dynamics in the CA1 pyramidal neurons (PNs) caused by the elevated α1-NaKA expression levels in the AS mice. Nonetheless, a causal link between hippocampal deficits and major behavioral phenotypes in AS is still obscure. Subiculum, a region adjacent to the hippocampal CA1 is the major output source of the hippocampus and plays an important role in the transfer of information from the CA1 region to the cortical areas. However, in spite of the robust hippocampal deficits and several known electrophysiological alterations in multiple brain regions in AS mice, the neuronal properties of the subicular neurons were never investigated in these mice. Additionally, subicular function is also implied in many neuropsychiatric disorders such as autism, schizophrenia, Alzheimer's disease, and epilepsy that share some common features with AS. Therefore, given the importance of the subiculum in these neuropsychiatric disorders and the altered electrophysiological properties of the hippocampal CA1 PNs projecting to the subiculum, we sought to examine the subicular PNs. We performed whole-cell recordings from dorsal subiculum of both WT and AS mice and found three distinct populations of PNs based on their ability to fire bursts or single action potentials following somatic current injection: strong bursting, weak bursting, and regular firing neurons. We found no overall differences in the distribution of these different subicular PN populations among AS and WT controls. However, the different cell types showed distinct alterations in their intrinsic membrane properties. Further, none of these populations were altered in their excitatory synaptic properties. Altogether, our study characterized the different subtypes of PNs in the subicular region of an AS mouse model.

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Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum.

Publications

Novel neurosteroid hypnotic blocks T-type calcium channel-dependent rebound burst firing and suppresses long-term potentiation in the rat subiculum.

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